Eukaryotic transcriptional regulation 1. Breast cancer We have followed up our recent discovery of a novel genetic pathway involved in establishment of phenotype of breast cancer cells. Briefly, we have discovered that estrogen receptor alpha (ER-alpha) regulates the synthesis of a rate limiting component of a transcriptional corepressor complex, the Mi-2/NuRD (Nucleosome remodeling deacetylase) complex. This complex is utilized by ER-alpha to assist in establishment of the genetic program integral to specification of an epithelial phenotype in normal mammary glands as well as in breast tumors. Mi-2/NuRD directly regulates the transcription factor Snail, which has the capacity to mediate epithelial to mesenchymal transitions (EMT). We have recently discovered that Snail can directly repress transcription of ER-alpha as part of the EMT program in breast cancer cells. 2. B lymphocyte development and differentiation We have identified an unexpected gene regulatory paradigm critical to the development and differentiation pathway of B lymphocytes. Following development of a mature B cell, antigen exposure leads, in the presence of the appropriate cytokine environment, to initiation of the T lymphocyte dependent germinal center reaction. During this process, B lymphocytes undergo the unique biology leading to affinity selection of immunoglobulins, ultimately differentiating into antibody secreting plasma cells. The proto-oncogene BCL6 is a transcriptional repressor necessary for B lymphocytes to undergo the germinal center reaction. We have discovered a direct interaction between BCL6 and the Mi-2/NuRD complex that is essential for the cell fate decisions that characterize the germinal center reaction. We are currently investigating the molecules involved in direct regulation of both BCL6 and the Mi-2/NuRD complex in developing B lymphocytes, in germinal center B lymphocytes, and in plasma cells.